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Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Background and Objective

The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 the highly specific CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.

Introduction

CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific CBP/β-catenin antagonists, ICG-001 and C82.

Methods

We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.

Results

Our data cast significant doubt that the mechanism of action of E7386 is specific CBP/β-catenin antagonism.

Conclusion

It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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2023-07-20
2024-11-23

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References

  1. EmamiK.H. NguyenC. MaH. KimD.H. JeongK.W. EguchiM. MoonR.T. TeoJ.L. KimH.Y. MoonS.H. HaJ.R. KahnM. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].Proc. Natl. Acad. Sci.200410134126821268710.1073/pnas.040487510115314234
     [Google Scholar]
  2. McMillanM. KahnM. Investigating Wnt signaling: A chemogenomic safari.Drug Discov. Today200510211467147410.1016/S1359‑6446(05)03613‑516243267
     [Google Scholar]
  3. KahnM. Taking the road less traveled – the therapeutic potential of CBP/β-catenin antagonists.Expert Opin. Ther. Targets202125970171910.1080/14728222.2021.199238634633266
     [Google Scholar]
  4. ThomasP.D. KahnM. Kat3 coactivators in somatic stem cells and cancer stem cells: Biological roles, evolution, and pharmacologic manipulation.Cell Biol. Toxicol.2016321618110.1007/s10565‑016‑9318‑027008332
     [Google Scholar]
  5. HuX. OnoM. ChimgeN.O. ChosaK. NguyenC. MelendezE. LouC.H. LimP. TerminiJ. LaiK.K.Y. FuegerP.T. TeoJ.L. HiguchiY. KahnM. Differential Kat3 usage orchestrates the integration of cellular metabolism with differentiation.Cancers20211323588410.3390/cancers1323588434884992
     [Google Scholar]
  6. RiegerM.E. ZhouB. SolomonN. SunoharaM. LiC. NguyenC. LiuY. PanJ. MinooP. CrandallE.D. BrodyS.L. KahnM. BorokZ. p300/β-catenin interactions regulate adult progenitor cell differentiation downstream of WNT5a/protein kinase C (PKC).J. Biol. Chem.2016291126569658210.1074/jbc.M115.70641626833564
     [Google Scholar]
  7. ZhaoY. MasielloD. McMillianM. NguyenC. WuY. MelendezE. SmbatyanG. KidaA. HeY. TeoJ-L. KahnM. CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells.Oncogene201635283705371710.1038/onc.2015.43826657156
     [Google Scholar]
  8. MiyabayashiT. TeoJ.L. YamamotoM. McMillanM. NguyenC. KahnM. Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency.Proc. Natl. Acad. Sci.2007104135668567310.1073/pnas.070133110417372190
     [Google Scholar]
  9. TeoJ.L. MaH. NguyenC. LamC. KahnM. Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation.Proc. Natl. Acad. Sci.200510234121711217610.1073/pnas.050460010216093313
     [Google Scholar]
  10. HiguchiY. NguyenC. YasudaS.Y. McMillanM. HasegawaK. KahnM. Specific direct small molecule p300/β-catenin antagonists maintain stem cell potency.Curr. Mol. Pharmacol.20169327227910.2174/187446720866615052615514626008738
     [Google Scholar]
  11. MaH. NguyenC. LeeK.S. KahnM. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression.Oncogene200524223619363110.1038/sj.onc.120843315782138
     [Google Scholar]
  12. KumarS.R. ScehnetJ.S. LeyE.J. SinghJ. KrasnoperovV. LiuR. ManchandaP.K. LadnerR.D. HawesD. WeaverF.A. BeartR.W. SinghG. NguyenC. KahnM. GillP.S. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression.Cancer Res.20096993736374510.1158/0008‑5472.CAN‑08‑323219366806
     [Google Scholar]
  13. El-KhoueiryA.B. NingY. YangD. ColeS. KahnM. ZoghbiM. BergJ. FujimoriM. InadaT. KoujiH. LenzH-J. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.J. Clin. Oncol.201331S15250110.1200/jco.2013.31.15_suppl.2501
     [Google Scholar]
  14. YamadaK. HoriY. YamaguchiA. MatsukiM. TsukamotoS. YokoiA. E7386: First-in-class orally active CBP/beta-catenin modulator as an anticancer agent.Cancer Res.201777S13
     [Google Scholar]
  15. YamadaK. HoriY. InoueS. YamamotoY. IsoK. KamiyamaH. YamaguchiA. KimuraT. UesugiM. ItoJ. MatsukiM. NakamotoK. HaradaH. YonedaN. TakemuraA. KushidaI. WakayamaN. KubaraK. KatoY. SembaT. YokoiA. MatsukuraM. OdagamiT. IwataM. TsuruokaA. UenakaT. MatsuiJ. MatsushimaT. NomotoK. KoujiH. OwaT. FunahashiY. OzawaY. E7386, a selective inhibitor of the interaction between β-catenin and CBP, exerts antitumor activity in tumor models with activated canonical wnt signaling.Cancer Res.20218141052106210.1158/0008‑5472.CAN‑20‑078233408116
     [Google Scholar]
  16. KandaY. OhataH. MiyazakiT. SakaiH. MoriY. ShiokawaD. YokoiA. OwaT. OchiaiA. OkamotoK. NF-κB suppression synergizes with E7386, an inhibitor of CBP/β-catenin interaction, to block proliferation of patient-derived colon cancer spheroids.Biochem. Biophys. Res. Commun.2022586939910.1016/j.bbrc.2021.11.06334837838
     [Google Scholar]
  17. ImaiT. NaruseM. OchiaiM. MatsumotoK. IkedaS. KaniM. KatoY. HirayamaA. SogaT. HoriY. YokoiA. OchiaiA. Different types of reactions to E7386 among colorectal cancer patient-derived organoids and corresponding CAFs.Oncol. Lett.202224122110.3892/ol.2022.1334235707761
     [Google Scholar]
  18. MouradovD. SloggettC. JorissenR.N. LoveC.G. LiS. BurgessA.W. ArangoD. StrausbergR.L. BuchananD. WormaldS. O’ConnorL. WildingJ.L. BicknellD. TomlinsonI.P.M. BodmerW.F. MariadasonJ.M. SieberO.M. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.Cancer Res.201474123238324710.1158/0008‑5472.CAN‑14‑001324755471
     [Google Scholar]
  19. ChenY. HuangB. ZhaoY. QiD. WangD. Increased p300/CBP expression in acute respiratory distress syndrome is associated with interleukin-17 and prognosis.Clin. Respir. J.2020149crj.1319710.1111/crj.1319732298537
     [Google Scholar]
  20. HammitzschA. TallantC. FedorovO. O’MahonyA. BrennanP.E. HayD.A. MartinezF.O. Al-MossawiM.H. de WitJ. VecellioM. WellsC. WordsworthP. MüllerS. KnappS. BownessP. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.Proc. Natl. Acad. Sci.201511234107681077310.1073/pnas.150195611226261308
     [Google Scholar]
  21. LiT.Y. SleimanM.B. LiH. GaoA.W. MottisA. BachmannA.M. AlamG.E. LiX. GoeminneL.J.E. SchoonjansK. AuwerxJ. The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress.Nature Aging20211216517810.1038/s43587‑020‑00025‑z33718883
     [Google Scholar]
  22. LillN.L. GrossmanS.R. GinsbergD. DeCaprioJ. LivingstonD.M. Binding and modulation of p53 by p300/CBP coactivators.Nature1997387663582382710.1038/429819194565
     [Google Scholar]
  23. GrossmanS.R. p300/CBP/p53 interaction and regulation of the p53 response.Eur. J. Biochem.2001268102773277810.1046/j.1432‑1327.2001.02226.x11358491
     [Google Scholar]
  24. SenP. LanY. LiC.Y. SidoliS. DonahueG. DouZ. FrederickB. ChenQ. LuenseL.J. GarciaB.A. DangW. JohnsonF.B. AdamsP.D. SchultzD.C. BergerS.L. Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence.Mol. Cell2019734684698.e810.1016/j.molcel.2019.01.02130773298
     [Google Scholar]
  25. LiY. ZhongH. WuM. TanB. ZhaoL. YiQ. XuX. PanH. BiY. YangK. Decline of p300 contributes to cell senescence and growth inhibition of hUC-MSCs through p53/p21 signaling pathway.Biochem. Biophys. Res. Commun.20195151243010.1016/j.bbrc.2019.05.06131122700
     [Google Scholar]
  26. Di GiorgioE. PaluvaiH. DallaE. RanzinoL. RenziniA. MoresiV. MinisiniM. PiccoR. BrancoliniC. HDAC4 degradation during senescence unleashes an epigenetic program driven by AP-1/p300 at selected enhancers and super-enhancers.Genome Biol.202122112910.1186/s13059‑021‑02340‑z33966634
     [Google Scholar]
  27. YangK. WangF. ZhangH. WangX. ChenL. SuX. WuX. HanQ. ChenZ. ChenZ.S. FuL. Target inhibition of CBP induced cell senescence in BCR-ABL- T315I mutant chronic myeloid leukemia.Front. Oncol.20211058864110.3389/fonc.2020.58864133585207
     [Google Scholar]
  28. PeiY. QianY. WangH. TanL. Epigenetic regulation of ferroptosis-associated genes and its implication in cancer therapy.Front. Oncol.20221277187010.3389/fonc.2022.77187035174081
     [Google Scholar]
  29. WortelI.M.N. van der MeerL.T. KilbergM.S. van LeeuwenF.N. Surviving stress: Modulation of ATF4-mediated stress responses in normal and malignant cells.Trends Endocrinol. Metab.2017281179480610.1016/j.tem.2017.07.00328797581
     [Google Scholar]
  30. GombartA.F. GrewalJ. KoefflerH.P. ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBPε and C/EBPα.J. Leukoc. Biol.20078161535154710.1189/jlb.080651617347301
     [Google Scholar]
  31. YukawaK. TanakaT. TsujiS. AkiraS. Regulation of transcription factor C/ATF by the cAMP signal activation in hippocampal neurons, and molecular interaction of C/ATF with signal integrator CBP/p300.Brain Res. Mol. Brain Res.199969112413410.1016/S0169‑328X(99)00086‑810350644
     [Google Scholar]
  32. LiangG. HaiT. Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein.J. Biol. Chem.199727238240882409510.1074/jbc.272.38.240889295363
     [Google Scholar]
  33. LassotI. EstrabaudE. EmilianiS. BenkiraneM. BenarousR. Margottin-GoguetF. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain.J. Biol. Chem.200528050415374154510.1074/jbc.M50529420016219772
     [Google Scholar]
  34. LiuY. DentinR. ChenD. HedrickS. RavnskjaerK. SchenkS. MilneJ. MeyersD.J. ColeP. IiiJ.Y. OlefskyJ. GuarenteL. MontminyM. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.Nature2008456721926927310.1038/nature0734918849969
     [Google Scholar]
  35. InabaM. YamashitaY.M. Asymmetric stem cell division: precision for robustness.Cell Stem Cell201211446146910.1016/j.stem.2012.09.00323040475
     [Google Scholar]
  36. VenkeiZ.G. YamashitaY.M. Emerging mechanisms of asymmetric stem cell division.J. Cell Biol.2018217113785379510.1083/jcb.20180703730232100
     [Google Scholar]
  37. KimuraK. IkomaA. ShibakawaM. ShimodaS. HaradaK. SaioM. ImamuraJ. OsawaY. KimuraM. NishikawaK. OkusakaT. MoritaS. InoueK. KantoT. TodakaK. NakanishiY. KoharaM. MizokamiM. Safety, tolerability, and preliminary efficacy of the anti-fibrotic small molecule PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus-related cirrhosis: A single-center, open-label, dose escalation phase 1 trial.EBioMedicine201723798710.1016/j.ebiom.2017.08.01628844410
     [Google Scholar]
  38. KimuraK. KantoT. ShimodaS. HaradaK. KimuraM. NishikawaK. ImamuraJ. OgawaE. SaioM. IkuraY. OkusakaT. InoueK. IshikawaT. IeiriI. KishimotoJ. TodakaK. KamisawaT. Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study.EBioMedicine20228010406910.1016/j.ebiom.2022.10406935605429
     [Google Scholar]
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E7386 is not a Specific CBP/β-Catenin Antagonist
Curr Mol Pharmacol 17, E290523217409 (2024); https://doi.org/10.2174/1874467217666230529114100
/content/journals/cmp/10.2174/1874467217666230529114100
/content/journals/cmp/10.2174/1874467217666230529114100
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  • Article Type:     Research Article
Keyword(s): Antagonism; C82; CBP; E7386; ICG-001; β-catenin

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